Liquid pharmaceutical compositions comprising sglt-2 inhibitors

ABSTRACT

The invention relates to novel liquid pharmaceutical compositions comprising at least one SGLT-2 inhibitor and one or more polar organic solvents, wherein the at least one SGLT-2 inhibitor comprises 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene according to formula (I): 
     
       
         
         
             
             
         
       
     
     as well as corresponding processes of manufacturing such liquid pharmaceutical compositions and their medical uses.

FIELD OF THE INVENTION

The invention relates to the field of medicine, particularly veterinarymedicine. In particular, the invention relates to novel pharmaceuticalcompositions comprising at least one SGLT-2 inhibitor.

BACKGROUND OF THE INVENTION

The treatment of diabetes and other metabolic disorders includes theinhibition of the renal sodium-dependent glucose co-transporter SGLT-2.SGLT-2 in the kidney regulates glucose levels by mediating thereabsorption of glucose back into the plasma following filtration of theblood. SGLT-2 inhibition thus induces glucosuria and may reduce bloodglucose levels.

A large variety of SGLT-2 inhibitors are known. A pharmaceuticalformulation of SGLT-2 inhibitors is essential in order to administersuch compounds in an adequate way to the patient.

SGLT-2 inhibitors are for instance described in WO 2007/028814 which isdirected to crystalline forms of1-chloro-4-([beta]-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene, amethod for the preparation thereof, as well as the use thereof forpreparing medicaments. It discloses solutions of1-chloro-4-([beta]-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene ina solvent or a mixture of solvents and further specifies exemplarilysuitable organic solvents such as ethanol or ethanol/water mixtures.

WO 2007/080170 describes crystalline forms of1′-(1-methylethyl)-4′-[(2-fluoro-4-methoxyphenyl)methyl]-5′-methyl-1H-pyrazol-3′-O-[beta]-D-glucopyranoside, a method forthe preparation thereof, as well as the use thereof for preparingmedicaments. It discloses solutions of1′-(1-methylethyl)-4′-[(2-fluoro-4-methoxyphenyl)methyl]-5′-methyl-1H-pyrazol-3′-O-[beta]-D-glucopyranoside in a solventor a mixture of solvents and further specifies exemplarily suitableorganic solvents such as ethanol or ethanol/water mixtures.

In addition, WO 2007/093610 describes glucopyranosyl-substitutedbenzonitrile derivatives, pharmaceutical compositions containing suchcompounds, their medical uses as well as processes for theirmanufacture. It mentions that such glucopyranosyl-substitutedbenzonitrile derivatives can be formulated among other with one or moreinert carriers and/or diluents, such as water/ethanol, water/glycerol,propylene glycol and the like. It further discloses among many othercompounds also1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene.

Further SGLT-2 inhibitors are described in WO 2007/128749 which relatesto glucopyranosyl-substituted benzonitrile derivatives, pharmaceuticalcompositions containing such compounds, their medical uses as well asprocesses for their manufacture. It mentions that suchglucopyranosyl-substituted benzonitrile derivatives can be formulatedamong other with one or more inert carriers and/or diluents, such aswater/ethanol, water/glycerol, propylene glycol and the like. It furtherdiscloses among many other compounds also1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene.

WO 2008/144316 describes crystal structures of a specificglucopyranosyl-substituted benzene derivative being an H-1 form, H-2form or the (S)-propylene glycol form. It discloses solutions of suchspecific glucopyranosyl-substituted benzene derivative in water-miscibleorganic solvents.

Another prior art document WO 2013/079501 is directed to crystallinedapagliflozin hydrate and a method for the preparation thereof. Itdiscloses solutions of dapagliflozin in a solvent or a mixture ofsolvents and further specifies exemplarily suitable solvents such aswater and C1-C4 alcohols or mixtures thereof.

WO 2014/016381 (US 2014/031540) describes crystalline complexes of1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene withnatural amino acids, methods for the preparation thereof as well as theuse thereof for preparing medicaments. It discloses solutions of1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene in asolvent or a mixture of solvents and further specifies exemplarilysuitable organic solvents such as C1-C4 alkanols, ethanol and mixturesthereof, in particular with water.

Furthermore, WO 2014/195966 describes amorphous forms of canagliflozinand processes of manufacturing thereof as well as correspondingpharmaceutical compositions and their medicinal uses. It disclosessolutions of canagliflozin in one or more organic solvents and furtherspecifies exemplarily suitable organic solvents such as ethanol.

Further challenges known in the prior art are the limited solubility ofSGLT-2 inhibitors in water due to their positive log₁₀P values, whichtypically influences the bioavailability in the body of a patient ormakes it difficult to find adequate solvents to get the substancedissolved in an liquid formulation before administering it into the bodyof a patient.

Further prior art is as follows:

Xu G et al. (Journal of Medical Chemistry 2014, 57: 1236-1251) isdirected to the design, synthesis and biological evaluation ofdeuterated C-aryl glycosides as potent and long-acting renal SGLT-2inhibitors for the treatment of type 2 diabetes.

WO 2015/110402 relates to SGLT-2 inhibitors for use in the treatmentand/or prevention of metabolic disorders in canine animals.

There is an urgent need for a directly administrable pharmaceuticalcomposition comprising at least one SGLT-2 inhibitor which overcomes theproblems of the prior art as described above.

SUMMARY OF THE INVENTION

The present invention concerns a liquid pharmaceutical compositioncomprising at least one SGLT-2 inhibitor and one or more polar organicsolvents, wherein the at least one SGLT-2 inhibitor comprises,preferably is,1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzeneaccording to formula (I):

wherein more preferably1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene isthe only SGLT-2 inhibitor contained in such liquid pharmaceuticalcomposition.

The present invention also concerns a liquid pharmaceutical compositionas described and claimed herein for use in a method for treating and/orpreventing one or more medicinal indications in a subject in need ofsuch treatment and/or prevention, preferably an animal, more preferablya mammal, in particular a horse, cat or dog, selected from among themedicinal indications:

-   -   (i) a metabolic disorder of an equine animal, wherein preferably        the metabolic disorder is one or more disorders selected from        insulin resistance, hyperinsulinemia, impaired glucose        tolerance, dyslipidemia, dysadipokinemia, subclinical        inflammation, systemic inflammation, low grade systemic        inflammation, obesity, and/or regional adiposity, wherein        preferably the metabolic disorder is insulin resistance,        hyperinsulinemia, and/or a clinical condition associated with        insulin resistance and/or hyperinsulinaemia; wherein preferably        said clinical condition is one or more conditions selected from        impaired glucose tolerance, dyslipidemia, dysadipokinemia,        subclinical inflammation, systemic inflammation, low grade        systemic inflammation, obesity, and/or regional adiposity;    -   (ii) a metabolic disorder of an equine animal, wherein the        metabolic disorder is one or more disorders selected from        laminitis, vascular dysfunction, hypertension, hepatic        lipidosis, atherosclerosis, hyperadrenocorticism, Pituitary Pars        Intermedia Dysfunction and/or Equine Metabolic Syndrome, wherein        preferably the metabolic disorder is a clinical condition/sign        associated with insulin resistance and/or hyperinsulinaemia,        wherein said clinical condition/sign preferably is one or more        conditions selected from laminitis, vascular dysfunction,        hypertension, hepatic lipidosis, atherosclerosis,        hyperadrenocorticism, Pituitary Pars Intermedia Dysfunction        and/or Equine Metabolic Syndrome;    -   (iii) a metabolic disorder of a feline animal, wherein        preferably the metabolic disorder is one or more selected from        the group consisting of: ketoacidosis, pre-diabetes, diabetes        mellitus type 1 or type 2, insulin resistance, obesity,        hyperglycemia, impaired glucose tolerance, hyperinsulinemia,        dyslipidemia, dysadipokinemia, subclinical inflammation,        systemic inflammation, low grade systemic inflammation, hepatic        lipidosis, atherosclerosis, inflammation of the pancreas,        neuropathy and/or Syndrome X (metabolic syndrome) and/or loss of        pancreatic beta cell function and/or wherein the remission of        the metabolic disorder, preferably diabetic remission, is        achieved and/or maintained;    -   (iv) a metabolic disorder of a canine animal, wherein preferably        the metabolic disorder is one or more selected from the group        consisting of: ketoacidosis, pre-diabetes, insulin dependent        diabetes mellitus, insulin resistance diabetes, insulin        resistance, obesity, hyperglycemia, hyperglycemia induced        cataract formation, impaired glucose tolerance,        hyperinsulinemia, dyslipidemia, dysadipokinemia, subclinical        inflammation, systemic inflammation, low grade systemic        inflammation, hepatic lipidosis, inflammation of the pancreas,        metabolic disorder consequences, such as hypertension, renal        dysfunction and/or musculoskeletal disorders, and/or Syndrome X        (metabolic syndrome), preferably pre-diabetes, insulin dependent        diabetes mellitus, insulin resistance diabetes, insulin        resistance, wherein preferably the development of hyperglycemia        induced cataract formation is prevented or remission is achieved        and/or wherein preferably the development of metabolic disorder        consequences, such as hypertension, renal dysfunction and/or        musculoskeletal disorders, is prevented or progression is slowed        or remission is achieved.

The present invention further concerns a process for producing theliquid pharmaceutical composition as described and claimed herein,comprising the steps:

-   -   (i) mixing the one or more polar organic solvents;    -   (ii) optionally, adding water to the mixture resulting from step        (i);    -   (iii) dissolving        1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene        in the mixture resulting from step (i) or optionally step (ii);    -   (iv) optionally, dissolving further excipients, such as pH        modifier(s), flavor(s), sweeteners, solubilizing agents,        viscosity-enhancing agents and the like, in the mixture        resulting from step (iii);    -   (v) optionally, filtrating the mixture resulting from step (iii)        or optionally step (iv);        whereby, optionally, independently from each other after any of        the individual process steps—be they mandatory or optional—an        additional mixing step is performed.

In the course of the present invention, such process steps (i) to (v) donot need to be carried out in the given order, but can also be performedin any other meaningful order, e.g. (ii)+(i)+(iv)+(iii)+(v). It iswithin the knowledge of the skilled person to vary the order of processsteps in order to obtain the desired process result, i.e. the liquidpharmaceutical composition according to the present invention. Forinstance, if one or more viscosity-enhancing agents are added, it ispreferred to heat the mixture up for complete dissolution of the one ormore viscosity-enhancing agents. In turn such resulting mixture needs tobe cooled down before the API1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene (inthe form of its L-proline-water cocrystal) is added in order to avoidunnecessary and unwanted degradation of the substance through suchheating steps.

The present invention further concerns a kit-of-parts comprising:

-   -   (a) a liquid pharmaceutical composition as described and claimed        herein; and    -   (b) a package leaflet including the information that the liquid        pharmaceutical composition is to be used for the prevention        and/or treatment of one or more medicinal indications in a        subject in need of such prevention and/or treatment, which are        selected from among the medicinal indications:        -   (i) a metabolic disorder of an equine animal, wherein            preferably the metabolic disorder is one or more disorders            selected from insulin resistance, hyperinsulinemia, impaired            glucose tolerance, dyslipidemia, dysadipokinemia,            subclinical inflammation, systemic inflammation, low grade            systemic inflammation, obesity, and/or regional adiposity,            wherein preferably the metabolic disorder is insulin            resistance, hyperinsulinemia, and/or a clinical condition            associated with insulin resistance and/or hyperinsulinaemia;            wherein preferably said clinical condition is one or more            conditions selected from impaired glucose tolerance,            dyslipidemia, dysadipokinemia, subclinical inflammation,            systemic inflammation, low grade systemic inflammation,            obesity, and/or regional adiposity;        -   (ii) a metabolic disorder of an equine animal, wherein the            metabolic disorder is one or more disorders selected from            laminitis, vascular dysfunction, hypertension, hepatic            lipidosis, atherosclerosis, hyperadrenocorticism, Pituitary            Pars Intermedia Dysfunction and/or Equine Metabolic            Syndrome, wherein preferably the metabolic disorder is a            clinical condition/sign associated with insulin resistance            and/or hyperinsulinaemia, wherein said clinical            condition/sign preferably is one or more conditions selected            from laminitis, vascular dysfunction, hypertension, hepatic            lipidosis, atherosclerosis, hyperadrenocorticism, Pituitary            Pars Intermedia Dysfunction and/or Equine Metabolic            Syndrome;        -   (iii) a metabolic disorder of a feline animal, wherein            preferably the metabolic disorder is one or more selected            from the group consisting of: ketoacidosis, pre-diabetes,            diabetes mellitus type 1 or type 2, insulin resistance,            obesity, hyperglycemia, impaired glucose tolerance,            hyperinsulinemia, dyslipidemia, dysadipokinemia, subclinical            inflammation, systemic inflammation, low grade systemic            inflammation, hepatic lipidosis, atherosclerosis,            inflammation of the pancreas, neuropathy and/or Syndrome X            (metabolic syndrome) and/or loss of pancreatic beta cell            function and/or wherein the remission of the metabolic            disorder, preferably diabetic remission, is achieved and/or            maintained;        -   (iv) a metabolic disorder of a canine animal, wherein            preferably the metabolic disorder is one or more selected            from the group consisting of: ketoacidosis, pre-diabetes,            insulin dependent diabetes mellitus, insulin resistance            diabetes, insulin resistance, obesity, hyperglycemia,            hyperglycemia induced cataract formation, impaired glucose            tolerance, hyperinsulinemia, dyslipidemia, dysadipokinemia,            subclinical inflammation, systemic inflammation, low grade            systemic inflammation, hepatic lipidosis, inflammation of            the pancreas, metabolic disorder consequences, such as            hypertension, renal dysfunction and/or musculoskeletal            disorders, and/or Syndrome X (metabolic syndrome),            preferably pre-diabetes, insulin dependent diabetes            mellitus, insulin resistance diabetes, insulin resistance,            wherein preferably the development of hyperglycemia induced            cataract formation is prevented or remission is achieved            and/or wherein preferably the development of metabolic            disorder consequences, such as hypertension, renal            dysfunction and/or musculoskeletal disorders, is prevented            or progression is slowed or remission is achieved.

The advantages of the liquid pharmaceutical compositions according tothe present invention are as follows:

-   -   They are suitable for direct administration to a subject without        further mandatory processing and/or purification steps.        Preferably they are therefore sterile and comply with GMP        manufacturing conditions as well as GCP compliant clinical        protocols.    -   They are stable against undesired contamination by/growth of        microorganisms.    -   Ethanol is not necessarily needed as polar organic solvent or        can be significantly reduced to a level which is expected to be        accepted by animals.

DETAILED DESCRIPTION OF THE INVENTION

Before the embodiments of the present invention are described in furtherdetails it shall be noted that as used herein and in the appendedclaims, the singular forms “a”, “an”, and “the” include plural referenceunless the context clearly dictates otherwise.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of ordinary skillin the art to which this invention belongs. All given ranges and valuesmay vary by 1 to 5% unless indicated otherwise or known otherwise by theperson skilled in the art, therefore, the term “about” was usuallyomitted from the description and claims. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present invention, the preferred methods,devices, and materials are now described. All publications mentionedherein are incorporated herein by reference for the purpose ofdescribing and disclosing the substances, excipients, carriers, andmethodologies as reported in the publications which might be used inconnection with the invention. Nothing herein is to be construed as anadmission that the invention is not entitled to antedate such disclosureby virtue of prior invention.

In the course of the present invention1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene isalso referred to as “the substance” and is herewith understood to alsocomprise co-crystal1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene-L-prolineas well as the co-crystal monohydrate1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene-L-proline-water(as disclosed in WO 2014/016381). Generally, in the case of disclosedand claimed mass concentrations (% w/w) and amounts (g, mg) the massconcentration or amount always refers to the “free base”1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene-L-proline,i.e. excluding L-proline and crystal water, unless otherwise explicitlystated—even though in practice (and in the example section) co-crystal1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene-L-proline-wateris actually added/used.

In the course of the present invention the term “suitable for directadministration to a subject” in connection with “liquid pharmaceuticalcomposition” means that such liquid pharmaceutical compositions can bedirectly administration to a subject without further mandatoryprocessing and/or purification steps and explicitly excludes (mixturesof) organic solvents that are solely mentioned in the context ofproducing crystalline complexes of SGLT2 inhibitors. Preferably, such“liquid pharmaceutical composition” that are “suitable for directadministration to a subject” are therefore sterile and/or comply withGMP manufacturing conditions as well as GCP compliant clinicalprotocols.

In one aspect, the present invention relates to a liquid pharmaceuticalcomposition as described and claimed herein, wherein the liquidpharmaceutical composition is suitable for direct administration to asubject, preferably an animal, more preferably a mammal, in particular ahorse, cat or dog; wherein preferably the liquid pharmaceuticalcomposition is sterile.

In another aspect, the present invention relates to a liquidpharmaceutical composition as described and claimed herein, wherein theliquid pharmaceutical composition is a solution, an emulsion or asuspension, preferably a solution, an emulsion or a suspension with anNTU value of equal to or less than 10.0, more preferably equal to orless than 7.0, even more preferably equal to or less than 3.0, and mostpreferably a solution, in particular a solution with an NTU value ofequal to or less than 3.0.

In the course of the present invention the term “NTU” refers toNephelometric Turbidity Units and to an opalescent value as defined anddescribed in European Pharmacopoeia 8^(th) edition (Ph. Eur. 8, Chapter2.2.1. “Clarity and degree of opalescence of liquids”).

In another aspect, the present invention relates to a liquidpharmaceutical composition as described and claimed herein, wherein theone or more polar organic solvents are independently from each othercharacterized by a negative log₁₀P value, preferably a negative decadiclogarithmic partition coefficient (P) in an n-octanol/water systemaccording to formula (II):

log₁₀ P _(n-octanol/water)=concentration of unionized compound inn-octanol/concentration of unionized compound in water  (II)

In a further aspect, the present invention relates to a liquidpharmaceutical composition as described and claimed herein, wherein suchliquid pharmaceutical composition as a whole is characterized by anegative Log P-Parameter, preferably a negative Log P-Parameter of equalto or less than −2.0 (i.e. −2.0≦Log P-Parameter<0). For the avoidance ofdoubt, the Log P-Parameter is defined as in Eq. 4 of Example 1 and isnot identical with and should not be mistaken for the (negative) log₁₀Pvalue as given for the one or more polar organic solvent(s).

In yet another aspect, the present invention relates to a liquidpharmaceutical composition as described and claimed herein, wherein theone or more polar organic solvents are selected from ethanol (log₁₀P:−0.16), propane-1,2-diol (propylene glycol; log₁₀P: −0.79),propane-1,2,3-triol (glycerol; log₁₀P: −1.84). The log₁₀P values weretaken from http://www.chemicalize.org/.

In yet another aspect, the present invention relates to a liquidpharmaceutical composition as described and claimed herein, wherein suchliquid pharmaceutical composition comprises at least two different polarorganic solvents, preferably two or three different polar organicsolvents, more preferably propane-1,2-diol (propylene glycol) andpropane-1,2,3-triol (glycerol) or ethanol and propane-1,2-diol(propylene glycol) or ethanol and propane-1,2-diol (propylene glycol)and propane-1,2,3-triol (glycerol). Preferably, if ethanol is present inthe liquid pharmaceutical composition as described and claimed herein,it is present at no more than 20 g/100 mL (20% w/w), preferably it ispresent at no more than 15 g/100 mL (15 w/w), more preferably it ispresent at no more than 10 g/100 mL (15% w/w), most preferably it ispresent at 8 g/100 mL (8% w/w).

In yet another aspect, the present invention relates to a liquidpharmaceutical composition as described and claimed herein, wherein suchliquid pharmaceutical composition does not comprise ethanol as the oneor more polar organic solvents.

In yet another aspect, the present invention relates to a liquidpharmaceutical composition as described and claimed herein, wherein suchliquid pharmaceutical composition does not comprise onlypropane-1,2-diol (propylene glycol) as single polar organic solvent.

In yet another aspect, the present invention relates to a liquidpharmaceutical composition as described and claimed herein, wherein suchliquid pharmaceutical composition additionally comprises water,preferably aqueous buffer, such as citric acid buffer (preferably withpH 6.0) or phosphate buffer (preferably with pH 6.8).

In yet another aspect, the present invention relates to a liquidpharmaceutical composition as described and claimed herein, wherein suchliquid pharmaceutical composition has a measured pH value of from 3 to9, preferably from 4 to 9, more preferably from 5.0 to 8.5, even morepreferably from 6.0 to 8.5 and most preferably from 6.0 to 7.5. For theavoidance of doubt, the term “measured pH value” refers to the pH valueactually measured for the whole liquid pharmaceutical compositionaccording to the present invention, although puristically only pH valuesof pure aqueous systems can be measured by means of standard pHdetermination methods.

In yet another aspect, the present invention relates to a liquidpharmaceutical composition as described and claimed herein, wherein suchliquid pharmaceutical composition additionally comprises one or moresolubilizing agents, preferably selected from the group consisting of:“surfactants, anionic surfactants, non-ionic surfactants, hydrogenatedcastor oils, polyoxyethylene-polyoxypropylene block copolymers,polyethylene glycols, propylenglycol derivatives”, more preferablyselected from the group consisting of: “Sodium dodecyl sulphate (SDS),Cremophor RH 40 (PEG-40 Hydrogenated Castor Oil, Macrogol glycerolhydroxystearate 40), polysorbate 20, Lutrol F 68 (Poloxamer 188), PEG300, propylenglycol monolaurate” and/or additionally comprises one ormore viscosity-enhancing agents, preferably selected from the groupconsisting of: “inorganic gel forming agents, organic gel formingagents, cellulose derivatives”, more preferably selected from the groupconsisting of: “hydroxyl ethyl cellulose, hydroxyl propyl methylcellulose, silicon dioxide” and/or additionally comprises one or moreflavors and/or sweeteners, preferably selected from the group consistingof: “honey flavor, lime/salvia flavor, jasmine flavor, lavender flavor,peppermint flavor, raspberry flavor, lemon flavor, herbs flavor,saccharine, aspartame”.

In yet another aspect, the present invention relates to a liquidpharmaceutical composition as described and claimed herein, wherein suchliquid pharmaceutical composition does not comprise any apolar organicsolvents, which are preferably and independently from each othercharacterized by a log₁₀P value of equal to or higher than 0.

In yet another aspect, the present invention relates to a liquidpharmaceutical composition as described and claimed herein, wherein suchliquid pharmaceutical composition is for oral and/or parenteraladministration, preferably oral administration.

In yet another aspect, the present invention relates to a liquidpharmaceutical composition as described and claimed herein, comprising

-   -   (i) 0.5-5.0 g/100 mL (% w/w), preferably 1.0-1.5 g/100 mL (%        w/w)        1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene;    -   (ii) 10-60 g/100 mL (% w/w), preferably 35-60 g/100 mL (% w/w),        more preferably 50-60 g/100 mL (% w/w) propylene glycol;    -   (iii) 0-60 g/100 mL (% w/w), preferably 0-52 g/100 mL (% w/w)        glycerol;    -   (iv) 0-20 g/100 mL (% w/w), preferably 0-15 g/100 mL (% w/w),        more preferably 0-10 g/100 mL (% w/w), most preferably 0-8 g/100        mL (% w/w) ethanol;    -   (v) 0-1 g/100 mL (% w/w), preferably 0-0.15 g/100 mL (% w/w)        flavor and/or sweetener, more preferably selected from the group        consisting of “honey flavor, lime/salvia flavor, jasmine flavor,        lavender flavor, peppermint flavor, raspberry flavor, lemon        flavor, herbs flavor, saccharine, and/or aspartame”;    -   (vi) 0-52 g/100 mL (% w/w), preferably 0-40 g/100 mL (% w/w)        aqueous buffer, preferably citric acid buffer pH 6.0 or        phosphate buffer pH 6.8;    -   (vii) 0-10 g/100 mL (% w/w), preferably 0-8 g/100 mL (% w/w)        solubilizing agent, preferably selected from the group        consisting of: “surfactants, anionic surfactants, non-ionic        surfactants, hydrogenated castor oils,        polyoxyethylene-polyoxypropylene block copolymers, polyethylene        glycols, and/or propylenglycol derivatives”, more preferably        selected from the group consisting of: “Sodium dodecyl sulphate        (SDS), Cremophor RH 40 (PEG-40 Hydrogenated Castor Oil, Macrogol        glycerol hydroxystearate 40), polysorbate 20, Lutrol F 68        (Poloxamer 188), PEG 300, and/or propylenglycol monolaurate”;    -   (viii) 0-5 g/100 mL (% w/w), preferably 0-0.5 g/100 mL (% w/w)        viscosity-enhancing agent, preferably selected from the group        consisting of “inorganic gel forming agents, organic gel forming        agents, and/or cellulose derivatives”, more preferably selected        from the group consisting of “hydroxyl ethyl cellulose, hydroxyl        propyl methyl cellulose, and/or silicon dioxide”.

In yet another aspect, the present invention relates to a liquidpharmaceutical composition as described and claimed herein, selectedfrom:

Composition 1 Composition 2 Composition 3 Composition 4 Composition 5Composition 6 Composition 7 Ingredient [% (w/w)] [% (w/w)] [% (w/w)] [%(w/w)] [% (w/w)] [% (w/w)] [% (w/w)] 1-cyano- 1.5 1.5 1.5 1.5 1.5 1.51.0 2-(4- cyclopropyl- benzyl)-4- (β-D- glucopyranos- 1-yl)- benzenePropylene 60 60 60 60 60 60 52 glycol Water 23.5 27.5 22.4 23.2 27.021.9 49.9 Glycerol 17.6 0.0 11.8 17.6 0.0 11.8 — 85% Ethanol, — 8 5 — 85 — abs. NaOH, 1N 4.71 5.51 4.49 4.63 5.41 4.39 — Citric 0.36 0.42 0.340.35 0.41 0.33 — acid, monohydrate Honey — — — 0.15 0.15 0.15 — flavorDisodium — — — — — — 0.890 hydrogen phosphate dodecahydrate Potassium —— — — — — 0.350 hydrogen phosphate

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the correlation of Turbidity and the Log P-Parameter(according to Example 1, Eq. 4) of solvent mixtures as depicted in Table2 used for preparing solutions of 1% (w/w) or 1.5% (w/w)1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene (thesubstance).

EXAMPLES

The following examples serve to further illustrate the presentinvention; but the same should not be construed as a limitation of thescope of the invention disclosed herein.

Example 1

The testing criteria applied are those for evaluation of the clarity ofa liquid (formulation) comprising1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzeneaccording to Pharm. Eur. 8. Concerning the Ph. Eur. 8, Chapter 2.2.1.“Clarity and degree of opalescence of liquids”, a liquid is consideredclear if its opalescence is not more pronounced than that of referencesuspension I having an opalescent value of 3 NTU (Table 1).

TABLE 1 Measurements of reference suspensions I-IV according Pharm. Eur.8, Chapter 2.2.1 Formazin suspensions Opalescent values (NTU) Referencesuspension I 3 Reference suspension II 6 Reference suspension III 18Reference suspension IV 30 Standard of opalescence 60 Primary opalescentsuspension 4000

In the following Table 2 exemplary pharmaceutical compositions ofsolvents which were mixed with1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene (thesubstance) according to the present invention are given in detail (Gly:glycerol; PG: propylene glycol, EtOH: ethanol). The turbidity wasmeasured by using a Hach Lange 2100 N IS apparatus.

The following procedure was used to prepare the samples:

-   -   1. Weigh entire amount of solvents into vessel    -   2. Weigh entire amount of buffer into the vessel, close the        vessel and mix it.    -   3. Weigh entire amount of        1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene        into the vessel, close the vessel and mix it over about 2        minutes.    -   4. Place the vessel into an ultrasonic bath until the solution        is particle free and free of air bubbles.    -   5. Measure turbidity and pH value

TABLE 2 Addition of the Instability Buffer Buffer substance at Gly PGEtOH Buffer pH pH [% Turbidity RT log₁₀P - V [%] [%] [%] [%] 6.8 6.0(m/m)] [NTU] pH observed Parameter 1 10.0 49.9 0.0 40.0 X — 1 2.2 7.6−1.6 2 10.1 39.9 0.0 50.0 X — 1 5.2 7.4 — −1.9 3 30.0 40.0 0.0 30.0 X —1 1.2 7.5 — −1.7 4 20.0 40.0 0.0 40.0 X — 1 2.0 7.4 — −1.8 5 10.1 44.90.0 45.0 X — 1 3.1 7.5 — −1.7 6 35.0 30.0 0.0 35.0 X — 1 3.2 7.3 — −2.07 30.0 35.0 0.0 35.0 X — 1 2.4 7.3 — −1.9 8 30.0 20.0 0.0 50.0 X — 134.3 7.1 Yes −2.7 9 20.0 30.0 0.0 50.0 X — 1 10.1 7.2 Yes −2.3 10 40.020.0 0.0 40.0 X — 1 9.5 7.2 Yes −2.4 11 30.0 10.0 0.0 60.0 X — 1 3.4 7.0Yes −3.8 12 20.1 35.0 0.0 45.0 X — 1 4.3 7.3 Yes −2.1 13 25.0 35.0 0.040.0 X — 1 4.0 7.5 — −2.0 14 30.0 30.0 0.0 40.0 X — 1 3.9 7.3 Yes −2.115 25.7 36.2 0.0 38.0 X — 1 3.5 7.4 — −1.9 16 40.0 50.0 0.0 10.0 X — 10.9 7.9 — −1.3 17 20.0 50.0 0.0 30.0 X — 1 2.7 7.6 — −1.5 18 25.0 45.10.0 29.9 X — 1 2.6 7.6 — −1.6 19 30.1 49.9 0.0 20.0 X — 1 1.3 7.7 — −1.420 35.0 45.0 0.0 20.0 X — 1 1.8 7.6 — −1.5 21 40.1 40.0 0.0 20.0 X — 11.8 8.0 — −1.6 22 50.0 50.0 0.0 0.0 X — 1 0.5 7.8 — −1.3 23 49.9 40.10.0 10.0 X — 1 0.6 — — −1.5 24 59.9 40.1 0.0 0.0 X — 1 0.6 — — −1.4 2510.0 60.0 0.0 30.0 X — 1.5 3.0 7.8 — −1.3 26 19.9 60.0 0.0 20.1 X — 1.52.0 7.9 — −1.3 27 0.0 60.0 5.0 35.0 X — 1.5 2.9 7.9 — −1.1 28 10.1 59.94.9 25.0 X — 1.5 2.0 7.9 — −1.1 29 20.0 59.9 5.0 15.0 X — 1.5 1.5 8.1 —−1.1 30 0.0 60.0 10.0 30.0 X — 1.5 2.1 8.1 — −0.9 31 10.0 60.0 10.0 20.0X — 1.5 1.6 8.2 — −1.0 32 20.0 60.0 10.0 10.0 X — 1.5 1.1 8.4 — −1.0 3315.0 59.9 0.0 25.0 X — 1.5 1.7 7.9 — −1.3 34 0.0 60.0 8.0 32.0 X — 1.51.7 8.0 — −1.0 35 15.0 60.0 2.5 22.6 X — 1.5 1.2 8.0 — −1.2 36 5.0 59.97.5 27.6 X — 1.5 1.7 8.0 — −1.0 37 14.2 56.8 0.0 28.9 — X 1.5 2.9 7.2 —−1.4 38 0.0 59.5 7.9 32.6 — X 1.5 2.4 7.3 — −1.0 39 9.7 58.1 4.8 27.4 —X 1.5 2.2 7.3 — −1.2

The mixtures of solvents applied for experiments V8 to V12 and V14showed instability phenomena like visible sediments in the solution oron the bottom of the vessel within 3 weeks short term storage at roomtemperature.

In order to quantify the solvent characteristics of these mixturesregarding their suitability to form a physical stable solution with thesubstance, a Log P-Parameter was introduced (Eq. 4). The Log P-Parameterdescribes the hydrophilic/hydrophobic nature of solvent mixturecontaining organic and aqueous solvents and is calculated as follows:

$\begin{matrix}{{Mo}_{i} = \frac{{mo}_{i}}{\sum\limits_{i = 1}^{n}{mo}_{i}}} & ( {{Eq}.\mspace{14mu} 1} ) \\{{{Log}\; {Po}} = {\sum\limits_{i = 1}^{\; n}( {{{Mo}_{i} \cdot {Log}}\; P_{i}} )}} & ( {{Eq}.\mspace{14mu} 2} ) \\{X_{o} = {1 - \frac{a_{w}}{a_{sol}}}} & ( {{Eq}.\mspace{14mu} 3} ) \\{{{Log}\; P\mspace{14mu} {Parameter}} = \frac{{Log}\; {Po}}{xo}} & ( {{Eq}.\mspace{14mu} 4} )\end{matrix}$

-   -   mo_(i) [mol/g]: molecular amount of an organic solvent in the        organic phase of a solvent mixture    -   Mo_(i) [-]: molecular fraction of organic solvent mo_(i) in the        organic phase of a solvent mixture    -   Log P_(i) [-]: log₁₀ P_(n-octanol/water)=concentration of        unionized compound in n-octanol/concentration of unionized        compound in water of an organic solvent    -   Log Po [-]: auxiliary parameter of the organic phase of a        solvent mixture    -   a_(w) [g]: mass of water or aqueous buffer in a solvent mixture    -   a_(sol) [g]: mass of solvent mixture    -   X_(o) [-]: mass fraction of organic phase in a solvent mixture

Exemplary Calculation

For glycerol the log₁₀P value (=Log P_(i)) is given as −1.84 and themolecular weight as 92.09 g/mol. 1 g of solvent mixture of V1 contains10% glycerol which corresponds to 0.1 g glycerol or 0.001086 mol(=mo_(glycerol)). The other organic solvent is propylene glycol (PG)having a log₁₀P value (=Log P_(i)) of −0.79 and a molecular weight of76.09 g/mol. 1 g of the solvent mixture of V1 contains 49.9% PG whichcorresponds to 0.499 g PG or 0.006558 mol (=mo_(PG)). Concerning Eq. 1Mo_(glycerol) is 0.142 and Mo_(PG) is 0.858. Log Po is calculated as−0.94 (Eq. 2). 1 g of solvent mixture of V1 contains 40% aqueous bufferwhich results in a mass fraction of organic phase of X_(o)=0.6 (Eq. 3).Following Eq. 4 a Log P-Parameter of −1.6 is calculated for the solventmixture of experiment V1. For mixtures containing ethanol, a log₁₀Pvalue (=Log P_(i)) for ethanol of −0.16 and a molecular weight of 46.07g/mol was used.

By correlating the measured Turbidity over the values for the LogP-Parameter between −3.0 and −0.5, an exponential function is observed(FIG. 1). Furthermore it was found, that solvent mixtures prepared withthe phosphate buffer pH 6.8 or the citric acid buffer pH 6.0 having aLog P-Parameter≧2.1 are physically instable after preparing a solutionwith the substance.

Example 2

In the following Table 3 exemplary pharmaceutical compositions accordingto the present invention are given in detail (API: active pharmaceuticalingredient).

TABLE 3 Exemplary pharmaceutical compositions according to the presentinvention Concentration Ingredient [g/100 mL (% w/w)] Function1-cyano-2-(4- 0.5-5.0; API cyclopropyl-benzyl)-4-(β- preferably 1.0-1.5D-glucopyranos-1-yl)- benzene Propylene glycol 10-60, Solvent preferably35-60; more preferably 50-60 Glycerol 0-60; Solvent preferably 0-52Ethanol, abs. 0-20; Solvent preferably 0-15; more preferably 0-10; mostpreferably 0-8 Flavor 0-1; Flavor preferably 0-0.15 Aqueous buffer 0-52;pH adjustment (e.g. citric acid buffer pH preferably 0-40 6.0 orphosphate buffer pH 6.8)

The production procedure of an exemplary pharmaceutical compositionaccording to the present invention for a single small scale batch (100mL) in form of a general instruction is as follows:

Prepare buffer solutionWeigh aqueous buffer solution in a vessel.Weigh propylene glycol and add to buffer solution under stirring.Weigh glycerol and add to the solution under stirring.Weigh ethanol and add to the solution under stirring.Weigh flavor and add to the solution under stirring.Weigh 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzeneand add in portions to the solution.Stir until fully dissolved.Filtration of the solution.

Example 3

Formulation samples were produced with compositions listed in thefollowing Table 4.

TABLE 4 Composition 1 Composition 2 Composition 3 Composition 4Composition 5 Composition 6 Composition 7 Ingredient [g/100 mL] [g/100mL] [g/100 mL] [g/100 mL] [g/100 mL] [g/100 mL] [g/100 mL] 1-cyano- 1.51.5 1.5 1.5 1.5 1.5 1.0 2-(4- cyclopropyl- benzyl)-4- (β-D-glucopyranos- 1-yl)- benzene Propylene 60 60 60 60 60 60 52 glycol Water23.5 27.5 22.4 23.2 27.0 21.9 49.9 Glycerol 17.6 0.0 11.8 17.6 0.0 11.8— 85% Ethanol. — 8 5 — 8 5 — abs. NaOH. 1N 4.71 5.51 4.49 4.63 5.41 4.39— Citric 0.36 0.42 0.34 0.35 0.41 0.33 — acid. monohydrate Honey — — —0.15 0.15 0.15 — flavor Disodium — — — — — — 0.890 hydrogen phosphatedodecahydrate Potassium — — — — — — 0.350 hydrogen phosphate

The following procedure was used to prepare the samples:

-   -   1. Weigh entire amount of water into vessel    -   2. Weigh entire amounts of NaOH 1N and citric acid monohydrate        or disodium hydrogen phosphate dodecahydrate and potassium        hydrogen phosphate into a beaker and add to stirred water. Stir        until fully dissolved.    -   3. Weigh entire amount of propylene glycol into a beaker and add        slowly to stirred solution.    -   4. Weigh entire amount of glycerol 85% into a beaker and add to        stirred solution. Stir until fully mixed.    -   5. Weigh entire amount of ethanol, abs. into a beaker and add to        stirred solution. Stir until fully mixed.    -   6. Weigh entire amount of flavor into a beaker and add to        stirred solution. Stir until fully dissolved.    -   7. Weigh entire amount of        1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene        into a beaker and add in portions to stirred solution. Stir        until fully dissolved.    -   8. Use a 8 μm Filter to filtrate the solution

The solutions were found to have the following densities and appearances(Table 5).

TABLE 5 Formulation/ Turbidity Density Solution [NTU] [g/mL] AppearanceComposition 1 1.8 1.077 yellowish, clear solution, no particlesComposition 2 1.6 1.029 yellowish, clear solution, no particlesComposition 3 1.5 1.055 yellowish, clear solution, no particlesComposition 4 1.3 1.077 yellowish, clear solution, no particlesComposition 5 1.1 1.028 yellowish, clear solution, no particlesComposition 6 1.1 1.054 yellowish, clear solution, no particlesComposition 7 5.8 1.046 yellowish, clear solution, no particles

Example 4

The testing criteria applied are those for evaluation of antimicrobialactivity for oral preparations according to Pharm. Eur. 7 (tests at 14days and 28 days). The acceptance criteria of the Ph. Eur. 7, Method5.1.3 “Efficacy of Antimicrobial Preservation”, and USP 34, Method <51>“Antimicrobial Effectiveness Testing” are listed in the following Table6.

TABLE 6 Criteria for evaluation of antimicrobial activity for oralpreparations according to Pharm. Eur. 7 and USP 34 Type Ph. Eur. 7Method 5.1.3. USP 34 Method <51> of micro- Logarithmic reduction ofmicroorganisms after organism 14 days 28 days 14 days 28 daysBacteria >3 No increase >1.0 No increase from 14 from 14 days ¹⁾ days ²⁾Fungi >1 No increase No increase No increase from 14 from initial frominitial days ¹⁾ calc. count ²⁾ calc. count ²⁾ ¹⁾ for Ph. Eur: Noincrease = no increase in number ²⁾ for USP: No increase = not more than0.5 log₁₀ units higher than reference value

The formulations tested in the trial are shown in the following Table 7.

TABLE 7 Trial 1 Trial 2 Trial 3 Trial 4 Trial 5 Trial 6 Ingredient[g/100 mL] [g/100 mL] [g/100 mL] [g/100 mL] [g/100 mL] [g/100 mL]1-cyano-2-(4- 1.5 1.5 1.5 1.5 1.5 1.5 cyclopropyl- benzyl)-4-(β-D-glucopyranos-1-yl)- benzene Propylene glycol 50.0 50.0 50.0 50.0 50.050.0 Glycerin 0.0 32.5 32.7 26.8 52.1 46.6 Ethanol abs. — — — 5.00 —5.00 Honey flavor 0.15 0.15 0.15 0.15 0.15 0.15 Propyl-hydroxy- 0.20 —0.20 — — — benzoate Phosphate buffer 52.2 20.0 20.0 20.0 — — pH 6.8After preparation of the samples, the solutions were filtrated via a0.22 μm filter. The following microorganisms were tested: Pseudomonasaeruginosa, Straphylococcus aureus, Escherichia coli, Candida albicans,Aspergillus brasiliensis, Zygosaccharomyces rouxi.

In the performed tests the USP 34 Method <51> Criteria as listed inTable 6 were found to be fulfilled for all solutions for allmicroorganisms. It was also found, that an additional preservative likepropyl-hydroxy-benzoate is not needed to get antimicrobialeffectiveness.

Example 5

Formulation samples were produced as follows:

-   1) Preparation of a basic excipient solution consisting of an    aqueous pH 6 phosphate buffer (21.05 mg/mL KH₂PO₄ and 8.82 mg/mL    Na₂HPO₄*12H₂O) and 20% (m/v) propylene glycol-   2) 1.34% (m/v)    1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene*L-proline*H₂O    (corresponds to 1.0%    1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene)    were dissolved in the basic excipient solution (batch size: 2000 mL)-   3) A solubilizing agent was weight into a 300 mL flask and filled up    to the mark with the solution

The following solubilizing agents were used:

Experiment 1: 0.1% (m/v) SDSExperiment 2: 1% (m/v) Cremophor RH 40Experiment 3: 1% (m/v) Lutrol F 68Experiment 4 8% (m/v) PEG 300For the experiments 1, 2, 3 and 4 no additional significant degradationare measured by HPLC analytics (table 8).

TABLE 8 Exper- Chemical byproduct/degradation measured by HPLC iment 3months at 25° C./60% r.h. 3 months at 40° C./75% r.h. 1 no no 2 no no 3no no 4 no no

Example 6

Formulation samples were produced as follows:

-   1) 1380 g propylene glycol and 619 g H₂O were mixed in a 3000 mL    beaker.-   2) 7.1 g hydroxyl ethyl cellulose, as a viscosity-enhancing agent,    was slowly added during intensive mixing with a propeller mixer.-   3) The mixture was kept for 30 minutes for swelling.-   4) The mixture was heated up to 70° C. during mixing and    additionally mixed for further 10 minutes at 70° C.-   5) The heater was switched off to cool down the mixture to room    temperature during stirring.-   6) 124.4 g NaOH 1N, 9.4 g citric acid monohydrate and 184 g ethanol    absolute were added during stirring at room temperature until the    solution is clear.-   7) 46.1 g    1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene*L-proline*H₂O    is added and stirred until the solution was clear.-   8) The mixture (called stock-solution) was filtered under pressure    with an 8 μm filter.

Trials with different flavors:

199.7 g stock-solution was filled in a separate beaker and 0.3 g offlavor was added (see table 9, experiments 2 to 7, experiment 1 is thestock solution).

Trials with different sweeteners:

199.98 g stock solution was filled in a separate beaker and 0.02 g ofsweetener was added (see Table 9, experiments 8 and 9).

TABLE 9 Exper- pH- Turbidity Density iment Flavor/sweetener value [NTU][g/ml] 1 Stock solution 7.1 1.8 1.029 2 Honey flavor 7.1 2.0 1.031 3Lime/Salvia flavor 7.2 1.9 1.031 4 Jasmine flavor 7.1 1.8 1.031 5Lavender flavor 7.2 1.9 1.031 6 Peppermint flavor 7.1 1.9 1.030 7Raspberry flavor 7.0 1.8 1.030 8 Saccharine 7.1 1.8 1.030 9 Aspartame7.1 1.8 1.032

For all depicted experiments the solutions are considered as clear(opalescent value<3 NTU, see Table 1).

REFERENCES

-   (1) European Pharmacopoeia 7^(th) edition, Method 5.1.3-   (2) European Pharmacopoeia 8^(th) edition, Chapter 2.2.1-   (3) United States Pharmacopeia (USP) 34, Method <51>-   (4) US 2014/031540-   (5) WO 2007/028814-   (6) WO 2007/080170-   (7) WO 2007/093610-   (8) WO 2007/128749-   (9) WO 2008/144316-   (10) WO 2013/079501-   (11) WO 2014/016381-   (12) WO 2014/195966-   (13) WO 2015/110402-   (14) Xu G et al., Journal of Medical Chemistry 2014, 57: 1236-1251

1. A liquid pharmaceutical composition comprising at least one SGLT-2inhibitor and one or more polar organic solvents, wherein the at leastone SGLT-2 inhibitor comprises,1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzeneaccording to formula (I):


2. The liquid pharmaceutical composition according to claim 1, wherein1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene isthe only SGLT-2 inhibitor contained in such liquid pharmaceuticalcomposition.
 3. The liquid pharmaceutical composition according to claim1, wherein said liquid pharmaceutical composition is suitable for directadministration to a mammal.
 4. The liquid pharmaceutical compositionaccording to claim 1, wherein said liquid pharmaceutical composition isa solution, an emulsion or a suspension.
 5. The liquid pharmaceuticalcomposition according to claim 1, wherein the one or more polar organicsolvents are independently from each other characterized by a negativelog₁₀P value.
 6. The liquid pharmaceutical composition according toclaim 1, wherein the one or more polar organic solvents are selectedfrom ethanol, propane-1,2-diol (propylene glycol), propane-1,2,3-triol(glycerol), and mixtures thereof.
 7. The liquid pharmaceuticalcomposition according to claim 1, wherein said liquid pharmaceuticalcomposition does not: (a) comprise ethanol as the one or more polarorganic solvents; or (b) comprise only propane-1,2-diol (propyleneglycol) as single polar organic solvent.
 8. The liquid pharmaceuticalcomposition according to claim 1, wherein said liquid pharmaceuticalcomposition additionally comprises water or an aqueous buffer.
 9. Theliquid pharmaceutical composition according to claim 8, wherein saidliquid pharmaceutical composition has a measured pH value of from 3 to9.
 10. The liquid pharmaceutical composition according to claim 1,wherein said liquid pharmaceutical composition additionally comprisesone or more solubilizing agents, one or more viscosity-enhancing agents,or one or more flavors or sweeteners.
 11. The liquid pharmaceuticalcomposition according to claim 1, wherein said liquid pharmaceuticalcomposition does not comprise any apolar organic solvents, which arepreferably and independently from each other characterized by a log₁₀Pvalue of equal to or higher than
 0. 12. The liquid pharmaceuticalcomposition according to claim 1, wherein such liquid pharmaceuticalcomposition is for oral or parenteral administration.
 13. The liquidpharmaceutical composition according to claim 1, comprising: (i) 0.5-5.0g/100 mL (% w/w)1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene; (ii)10-60 g/100 mL (% w/w) propylene glycol; (iii) 0-60 g/100 mL (% w/w)glycerol; (iv) 0-20 g/100 mL (% w/w) ethanol; (v) 0-1 g/100 mL (% w/w)flavor and/or sweetener; (vi) 0-52 g/100 mL (% w/w) aqueous buffer;(vii) 0-10 g/100 mL (% w/w) solubilizing agent; and (viii) 0-5 g/100 mL(% w/w) viscosity-enhancing agent.
 14. The liquid pharmaceuticalcomposition according to claim 13 selected from the group consisting ofthe following compositions 1 to 7: Composition 1 Composition 2Composition 3 Composition 4 Composition 5 Composition 6 Composition 7Ingredient [% (w/w)] [% (w/w)] [% (w/w)] [% (w/w)] [% (w/w)] [% (w/w)][% (w/w)] 1-cyano- 1.5 1.5 1.5 1.5 1.5 1.5 1.0 2-(4- cyclopropyl-benzyl)-4- (β-D- glucopyranos- 1-yl)- benzene Propylene 60 60 60 60 6060 52 glycol Water 23.5 27.5 22.4 23.2 27.0 21.9 49.9 Glycerol 17.6 0.011.8 17.6 0.0 11.8 — 85% Ethanol, — 8 5 — 8 5 — abs. NaOH, 1N 4.71 5.514.49 4.63 5.41 4.39 — Citric 0.36 0.42 0.34 0.35 0.41 0.33 — acid,monohydrate Honey — — — 0.15 0.15 0.15 — flavor Disodium — — — — — —0.890 hydrogen phosphate dodecahydrate Potassium — — — — — — 0.350hydrogen phosphate


15. The liquid pharmaceutical composition according to claim 1 for usein a method for treating or preventing medicinal indications in a mammalin need of such treatment or prevention selected from among themedicinal indications: (i) a metabolic disorder of an equine animal,wherein the metabolic disorder is selected from the group consisting of:insulin resistance, hyperinsulinemia, impaired glucose tolerance,dyslipidemia, dysadipokinemia, subclinical inflammation, systemicinflammation, low grade systemic inflammation, obesity, regionaladiposity, and mixtures thereof; (ii) a metabolic disorder of an equineanimal, wherein the metabolic disorder is selected from the groupconsisting of: laminitis, vascular dysfunction, hypertension, hepaticlipidosis, atherosclerosis, hyperadrenocorticism, Pituitary ParsIntermedia Dysfunction, Equine Metabolic Syndrome and mixtures thereof;(iii) a metabolic disorder of a feline animal, wherein the metabolicdisorder is selected from the group consisting of: ketoacidosis,pre-diabetes, diabetes mellitus type 1 or type 2, insulin resistance,obesity, hyperglycemia, impaired glucose tolerance, hyperinsulinemia,dyslipidemia, dysadipokinemia, subclinical inflammation, systemicinflammation, low grade systemic inflammation, hepatic lipidosis,atherosclerosis, inflammation of the pancreas, neuropathy, Syndrome X(metabolic syndrome), loss of pancreatic beta cell function and mixturesthereof; (iv) a metabolic disorder of a canine animal, wherein themetabolic disorder is selected from the group consisting of:ketoacidosis, pre-diabetes, insulin dependent diabetes mellitus, insulinresistance diabetes, insulin resistance, obesity, hyperglycemia,hyperglycemia induced cataract formation, impaired glucose tolerance,hyperinsulinemia, dyslipidemia, dysadipokinemia, subclinicalinflammation, systemic inflammation, low grade systemic inflammation,hepatic lipidosis, inflammation of the pancreas, metabolic disorderconsequences, such as hypertension, renal dysfunction, musculoskeletaldisorders, Syndrome X (metabolic syndrome), and mixtures thereof.
 16. Aprocess for producing the liquid pharmaceutical composition according toclaim 1, comprising the steps: (i) mixing the one or more polar organicsolvents; and (ii) dissolving1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene inthe mixture resulting from step (i).
 17. A kit-of-parts comprising: (a)a liquid pharmaceutical composition according to claim 1; and (b) apackage leaflet including the information that the liquid pharmaceuticalcomposition is to be used for the prevention or treatment of one or moremedicinal indications in a subject in need of such prevention ortreatment, which are selected from among the medicinal indications: (i)a metabolic disorder of an equine animal, wherein the metabolic disorderis selected from the group consisting of: insulin resistance,hyperinsulinemia, impaired glucose tolerance, dyslipidemia,dysadipokinemia, subclinical inflammation, systemic inflammation, lowgrade systemic inflammation, obesity, regional adiposity, and mixturesthereof; (ii) a metabolic disorder of an equine animal, wherein themetabolic disorder is selected from the group consisting of: laminitis,vascular dysfunction, hypertension, hepatic lipidosis, atherosclerosis,hyperadrenocorticism, Pituitary Pars Intermedia Dysfunction, EquineMetabolic Syndrome and mixtures thereof; (iii) a metabolic disorder of afeline animal, wherein the metabolic disorder is selected from the groupconsisting of: ketoacidosis, pre-diabetes, diabetes mellitus type 1 ortype 2, insulin resistance, obesity, hyperglycemia, impaired glucosetolerance, hyperinsulinemia, dyslipidemia, dysadipokinemia, subclinicalinflammation, systemic inflammation, low grade systemic inflammation,hepatic lipidosis, atherosclerosis, inflammation of the pancreas,neuropathy, Syndrome X (metabolic syndrome), loss of pancreatic betacell function and mixtures thereof; (iv) a metabolic disorder of acanine animal, wherein the metabolic disorder is selected from the groupconsisting of: ketoacidosis, pre-diabetes, insulin dependent diabetesmellitus, insulin resistance diabetes, insulin resistance, obesity,hyperglycemia, hyperglycemia induced cataract formation, impairedglucose tolerance, hyperinsulinemia, dyslipidemia, dysadipokinemia,subclinical inflammation, systemic inflammation, low grade systemicinflammation, hepatic lipidosis, inflammation of the pancreas, metabolicdisorder consequences, such as hypertension, renal dysfunction,musculoskeletal disorders, Syndrome X (metabolic syndrome), and mixturesthereof.
 18. The liquid pharmaceutical composition according to claim 3,wherein the mammal is a horse, cat or dog.
 19. The liquid pharmaceuticalcomposition according to claim 3, wherein said liquid pharmaceuticalcomposition is sterile.
 20. The liquid pharmaceutical compositionaccording to claim 4, wherein said solution, an emulsion or a suspensionhas an NTU value of equal to or less than 10.0.
 21. The liquidpharmaceutical composition according to claim 5, wherein said liquidpharmaceutical composition is independently of each other characterizedby a negative decadic logarithmic partition coefficient (P) in ann-octanol/water system according to formula (II):log₁₀ P _(n-octanol/water)=concentration of unionized compound inn-octanol/concentration of unionized compound in water  (II).
 22. Theliquid pharmaceutical composition according to claim 21, wherein saidliquid pharmaceutical composition as a whole is characterized by anegative Log P-Parameter of equal to or less than −2.0 (−2.0≦LogP-Parameter<0).
 23. The liquid pharmaceutical composition according toclaim 10, wherein preferably said one or more solubilizing agents areselected from the group consisting of: surfactants, anionic surfactants,non-ionic surfactants, hydrogenated castor oils,polyoxyethylene-polyoxypropylene block copolymers, polyethylene glycols,propylenglycol derivatives and mixtures thereof.
 24. The liquidpharmaceutical composition according to claim 23, wherein said one ormore solubilizing agents are selected from the group consisting of:Sodium dodecyl sulphate (SDS), Cremophor RH 40 (PEG-40 HydrogenatedCastor Oil, Macrogol glycerol hydroxystearate 40), polysorbate 20,Lutrol F 68 (Poloxamer 188), PEG 300, propylenglycol monolaurate andmixtures thereof.
 25. The liquid pharmaceutical composition according toclaim 10, wherein said one or more viscosity-enhancing agents areselected from the group consisting of: inorganic gel forming agents,organic gel forming agents, cellulose derivatives, and mixtures thereof.26. The liquid pharmaceutical composition according to claim 25, whereinsaid one or more viscosity-enhancing agents are selected from the groupconsisting of: hydroxyl ethyl cellulose, hydroxyl propyl methylcellulose, silicon dioxide, and mixtures thereof.
 27. The liquidpharmaceutical composition according to claim 10, wherein said one ormore flavors or sweeteners are selected from the group consisting of:honey flavor, lime/salvia flavor, jasmine flavor, lavender flavor,peppermint flavor, raspberry flavor, lemon flavor, herbs flavor,saccharine, aspartame, and mixtures thereof.
 28. The process forproducing the liquid pharmaceutical composition according to claim 16,further comprising adding water to the mixture resulting from step (i).29. The process for producing the liquid pharmaceutical compositionaccording to claim 16, further comprising dissolving said1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene inthe mixture resulting from step (i) or step (ii).
 30. The process forproducing the liquid pharmaceutical composition according to claim 16,further comprising dissolving further excipients in the mixtureresulting from step (iii).
 31. The process for producing the liquidpharmaceutical composition according to claim 16, further comprisingfiltrating the mixture resulting from step (iii) or optionally step(iv).
 32. The process for producing the liquid pharmaceuticalcomposition according to claim 16, further comprising an additionalmixing step is performed after each step.